GB2177921A

GB2177921A - Synergistic gastric composition

Info

Publication number: GB2177921A
Application number: GB08616704A
Authority: GB
Inventors: Aws Shakir Mustafa Salim
Original assignee: Individual
Current assignee: Individual
Priority date: 1985-07-09
Filing date: 1986-07-09
Publication date: 1987-02-04
Also published as: GB2177921B; GB8616704D0; US4959369A; GB8517302D0

Abstract

A pharmaceutical composition for use in improving the condition of gastro-intestinal mucosa comprises an S- methyl substituted ternary sulphonium derivative of methionine and cysteine.

Description

1 4 1 1 r 40 GB 2 177 921 A 1

SPECIFICATION Synergistic Gastric Composition

The present invention relates to the treatment of gastric mucosa.

It has previously been proposed to use methyl methionine sulfonium chloride (conveniently referred to as MMSC) in the treatment of gastric mucosal injuries such as ulcers.

It has now surprisingly been found that the activity of S-methyl substituted ternary sulfonium derivatives of methionine, such as MMSC, is substantially enhanced when such a derivative is used in combination with cysteine, and that such combinations exhibit synergism, that is a greater activity then that corresponding to the sum of the components of the combination when used 80 individually.

Thus the present invention provides a combination for use in improving the condition of gastro-intestinal mucosa which combination comprises an S-methyl substituted ternary 85 sulphonium derivative of methionine and cysteine.

The components of the combinations of the invention may be used in a wide range of different proportions relative to each other. In general though they are used in the range of from 1 to 5 parts by weight of the methionine derivative to one part by weight of eysteine.

It will be noted that at least some of the abovementioned compounds have one or more optically active centres, in particular in the case of the amino acids at the amino- and carboxyl substituted carbon. For the avoidance of doubt therefore it is observed that the present invention extends to both individual isomers such as D- and L isomers and enantiomers, and, in the case where two or more optically active centres are present, diastereoisomers, as well as mixtures of isomers including racemic DL mixtures.

Whilst not restricting the scope of the invention in 105 anyway it is believed by the inventor that the effectiveness of the agents of the invention is due at least in partto their ability to scavenge free radicals to a greater or lesser extent and hence prevent or reduce damage to skin caused by these.

In accordance with the present invention the application of combinations of the invention to gastric mucosa has been found to improve condition in a number of ways including improved healing of wounds and ulcers, and protection against non-mechanical injury e.g. from injurious chemical materials.

Advantageously there may also be included an antiischaemic substance and in particular papaverine, and/or an anti-cholinergic and/or vagal 120 nerve blocking substance, especially one or more compounds selected from propoxycaine and amethocaine.

In a further aspectthe present invention provides a combination of the invention in intimate admixture with a physiologically acceptable carrier therefor for use in improving the condition of gastric mucosa.

In another aspect the present invention provides a f-, 5 topical formulation comprising a combination of the invention in intimate admixture with a phar6aceutically acceptable vehicle therefor. The vehicle should be "acceptable" in the sense of being generally nondeleterious to the gastric mucosa of the subject being treated and compatible with the other ingredients of the formulation. The combinations of the invention (optionally with other active ingredients and/or a suitable vehicle) are generally administered orally. 75 For oral administration the combination of the invention and any accompanying material may be presented as a draught in water or in a syrup, in capsules, cachets, boluses or tablets, as an aqueous or oleaginous solution or suspension or in suspension in a syrup, such suspensions optionally including suspending agents or as an oil-in-water or water-in-oil emulsion. Where desirable or necessary flavouring, sweetening, preserving, thickening or emulsifying agents may be included in the formulation. Tablets may contain combinations of the invention and any accompanying material as a powder or granules optionally mixed with binders, lubricants, inert diluents or surface- active or dispersing agents. go For administration orally in liquid form or parenterally the combination of the invention is preferably presented in solution or suspension or emulsion at a concentration of from 5 to 25 more preferably 10 to 12 w/v in unit multiclose form. When presented in unit dose form each unit dose preferably contains from 200 to 1200 mg of the combination of the invention, preferably from 400 to 600 mg.

In general for the purposes of treating gastro- intestinal mucosa the combination of the invention is administered at a dosage rate of from 20 to 100 mg/kg of subject bodyweight per day, preferably from 30 to 40 mg/kg/day. The dosage may be administered in one or more doses per day and preferably is administered at intervals of from 2 to 6 hours, most preferably every 4 hours. Advantageously the combination of the invention is administered in a slow release or sustained release vehicle, various suitable vehicles of this type be ing known in the art.

Where papaverine is included this is generally used at a dosage rate of the order of 1 mg/kg/day.

The present invention also provides a process for producing a pharmaceutical formulation of the invention comprising bringing into intimate association a combination of the invention and a pharmaceutically acceptable vehicle therefor. Combinations of the invention may be administered to human beings to improve gastric mucosal condition and the present invention accordingly extends to a method of improving the condition of gastric mucosa comprising administration of an effective dosage of a combination of the invention to the gastric mucosa. 125 Where skin is being treated the procaine will normally be applied in the form of a topical formulation of the invention at least once a day, preferably 2 or 3 times a day. The formulation is 2 GB 2 177 921 A 2 generally spread over the area to be treated and gently rubbed in.

Further preferred features and advantages of the invention will appearfrom the following detailed examples given by way of illustration only.

EXAMPLE 1

Preparation of Capsules for Oral Administration The following composition was prepared in a glass container screened off from any direct light and at a room temperature of 260C by mixing methyimethione sulfonium chloride (500 mg) and cysteine (100 mg) (per capsule) powderform and then filling the 600 mg of the mixture into each gelatinous capsule. The filled capsules were then stored in opaque containers away from direct light and at a room temperature of 260C. All capsules were used within six months of preparation. 60 EXAMPLE 2 Activity of M MSC with Cysteine The activity of MMSC (100 mg/kg) and cysteine (100 mg/kg) given together was assessed in the reserpine-induced gastric mucosal injury rat.

Male and female Sprague-Dawley rats weighing 220-260 g were used. Animals were deprived of food, but not water, for 24 hours before experiments. The surface area (MM2) of gastric mucosa occupied by rnucosal injury was determined by an independent scorer unaware of the experimental procedure. In a pilot study using two groups of each of ten rats, reserpine given intraperitoneally in a dose of 5 mg/kg produced after 75 six hours acute gastric mucosal injury confined to the glandular stomach in all members of both groups. Sixty animals were then injected with reserpine 5 mg/kg intraperitoneally. Following injections animals were divided at random into six groups each of ten rats. Six hours after injections animals were allowed food ad libitum. Twelve hours after completion of injections three groups were started on intraperitoneal saline 5 mi/kg and the remaining three groups were started on intraperitoneal MMSC 100 mg/kg and cysteine 100 mg/kg. Saline, MMSC and cysteine were administered at 24 hour intervals over 6 successive days. One group of the saline treated animals and another of the MMSC with cysteine treated animals were sacrificed on the 2nd, 4th and 6th days following initiation of injections with these drugs. While MMSC with cysteine had no effect on the surface area (MM2) of reserpine-induced gastric mucosal injury on the 2nd day following treatment, they significantly healed the mentioned injury relative to controls (saline groups) on both the 4th (P<0.05) and 6th (P<0.01) days following treatment.

Claims

1. A combination for use in improving the condition of gastro-intestinal mucosa which combination comprises an S-methyl substituted ternary sulphonium derivative of methionine and cysteine.

2. A combination as claimed in claim 1 wherein said methionine derivative comprises methyl methionine sulfonium chloride.

3. A combination as claimed in claim 1 or claim 2 which includes at least one of an anti-ischaemic substance, an anti- cholinergic substance, and a vagal nerve blocking substance.

4. A combination as claimed in claim 3 which includes at least one papaverine, propoxycaine and amethocaine.

5. A combination for use in improving the condition of gastro-intestinal mucosa substantially as described hereinbefore with particular reference to Example 1.

6. A pharmaceutical composition suitable for use in improving the condition of gastro-intestinal mucosa comprising a combination as claimed in any one of the preceding claims in intimate admixture with a physiologically acceptable carrier therefor.

7. A composition as claimed in claim 6 which is in the form of an oral formulation.

8. A combination as claimed in any one of claims 1 to 5 for use in the preparation of a medicament for improving the condition of gastro-intestinal mucosa.

Printed for Her Majesty's Stationery Office by Courier Press, Leamington Spa. 211987. Demand No. 8817356. Published by the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.

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